As used herein, the term "immunostimulant" means a composition which is capable of stimulating a non-specific immune response in an animal or human. As used herein, "reproductive performance" means an increase in number of offspring, an increase in survival rate of offspring, an increase in first service conception rate and a decrease in service number per conception. As used herein, "apparently infertile" means infertility diagnosed by the clinical criteria applicable to a particular species of animal or to a human.
The immune response involves the whole body and is modulated and affected by many complex interactions. Nonspecific immune stimulation is capable of accelerating and amplifying many immune responses. Immunostimulants of bacterial, yeast, viral, plant, chemical and biotechnological origin may be used to non-specifically stimulate immune activity. Immunostimulants derived from Mycobacteriacae and Actinomycetaceae including Mycobacterium, Corynebacterium (Proprionebacterium), Nocardia, Rhodococcus, other Coryneform bacteria, Bordetella, Listeria, and bacille Calmette-Guerin (BCG) have been used to non-specifically stimulate immune activity.
Two components relevant to non-specific immunostimulant activity have been identified and isolated from the bacille Calmette-Guerin (BCG). N-Acetyl-muramyl-alanyl-3-isoglutamine (muramyl dipeptide) is a small component of the mycobacterial cell wall that can mediate the immunostimulant activity produced by whole mycobacteria in the water-in-oil emulsion of Freund's complete adjuvant. Muramyl dipeptide can activate macrophages and potentiate T-and B-cell-mediated reactions. Trehalose dimycolate is another component of mycobacteria that has immunostimulant activity.
Whether large complex molecules like peptidoglycans and lipopolysaccharides or simple molecules such as muramyl dipeptide and trehalose dimycolate are used, the common pathway points to macrophage and monocyte activation as the mechanism of immunostimulant activity. Activation of macrophages and monocytes results in increased synthesis and release of bioactive proteins and lipids which initiate, accelerate and amplify the immune response.
The non-specific immunostimulant activity of preparations from microorganisms has been studied extensively. Bacterial cell wall extracts have been used to treat diseases of the skin (U.S. Pat. No. 4,340,586), bacterial infections (U.S. Pat. No. 3,172,815), tumors (U.S. Pat. No. 4,503,048), and virus infections (U.S. Pat. No. 4,744,984) in animals and humans. Immune stimulation has been used in contraception and abortion (U.S. Pat. No. 5,006,334).
Reproductive performance is of great importance in enterprises where the breeding of animals is necessary for the commercial success of the enterprise. Reproductive performance also is of great importance to humans attempting to conceive a child. Attempts to increase reproductive performance have largely focused on the use of reproductive hormones to manipulate reproductive performance. These attempts include, but are not limited to, stimulation of reproductive hormone synthesis and secretion, induction of ovulation and/or superovulation using purified and/or synthetic hormones, artificial insemination and, more recently, the use of in vitro fertilization and embryo transfer techniques. These methodologies have provided various degrees of success in increasing reproductive performance in different species. Each of these methodologies, however, is labor intensive and requires sophisticated and expensive technologies for its implementation.
Immune cells respond to the cyclically changing hormonal environment within reproductive tissues so that major events such as ovulation, implantation and parturition resemble an inflammatory and reparative response to infection. Likewise, reproductive tissues respond to bioactive proteins and lipids produced by immune cells so that a complex of interactions among neuroendocrine hormones, macrophages, fibroblasts, reproductive tissue cells and other cells participate in the coordination of reproduction.
For example, ovulation can be described as an immune inflammatory reaction (Epsey, L.L ., 1980, Ovulation As An Inflammatory Reaction-A Hypothesis, Biol. Reprod. 22:73-106). Inflammatory exudates containing mitogenic factors may stimulate DNA synthesis and cell division in quiescent follicles (Epsey, L. L., 1980, Ovulation As An Inflammatory Reaction-A Hypothesis, Biol. Reprod. 22:73-106). Interleukins may increase the expression of luteinizing hormone (LH) receptors on mature follicles and may sensitize follicles to LH thereby increasing ovulatory rates. Further, interleukins may have a regulatory role in the transition of granulosa cell to luteal cells in the ovary (Sjogren et al., 1991, Interleukin-la Modulates Luteinizing Hormone Stimulated Cyclic AMP and Progesterone Release From Human Granulosa Cells In Vitro, Human Reprod. 6:910-913). Interleukins also may sensitize testicular Leydig cells to luteinizing hormone and increase spermatogenesis.
Implantation also can be described as an immune inflammatory response (Finn, C. A., 1986, Implantation, Menstruation and Inflammation, Biol. Rev. 61:3213-28). Oestrogen and progesterone regulate the expression of leukemia inhibitory factor and cytokines by uterine epithelial cells and both leukemia inhibitory factor and cytokines are necessary for zygote implantation (Stewart et al., 1992, Blastocyte Implantation Depends on Maternal Expression of Leukemia Inhibitory Factor, Nature 359:76-79). Cytokines also may be embryotrophic factors which enhance communication between the developing embryo and the mother (Mogil et at., 1988, Maternal Immune Reactivity as a Determinant of Placental Function and Fetal Survival, Sem. Reprod. EndocrinoI. 6:145-154). In fact, insufficient production of cytokines has been implicated in increased embryonic death (Chaouat et at., 1990, Control of Fetal Survival in CBA-X DBA/2 Mice by Lymphokine Therapy, J. Reprod. FertiI. 89:447-458). Cytokines also may play a major role in the inflammatory events of parturition and postnatal repair.
Thus, what is needed is a composition and method of use that is effective for stimulating the immune system of an animal or human in such as way as to increase the reproductive performance of the animal or human.